Molecular imaging-guided repair after acute myocardial infarction by targeting the chemokine receptor CXCR4

Author:

Hess Annika1ORCID,Derlin Thorsten1ORCID,Koenig Tobias2,Diekmann Johanna1ORCID,Wittneben Alexander1,Wang Yong2,Wester Hans-Juergen3,Ross Tobias L1ORCID,Wollert Kai C2ORCID,Bauersachs Johann2ORCID,Bengel Frank M1ORCID,Thackeray James T1ORCID

Affiliation:

1. Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

2. D epartment of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany

3. Radiopharmaceutical Chemistry, Technical University of Munich, Walther-Meissner-Str. 3, 85748 Garching, Germany

Abstract

Abstract Aims  Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. Methods and results  Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = −0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. Conclusion  Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.

Funder

German Research Foundation

DFG

Clinical Research Group

Excellence Cluster REBIRTH-2

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine

Reference27 articles.

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